3-Isopropenyl-6-heptenoic acid

ABSTRACT

Synthesis and intermediates for making insect pheromone useful in the control of red scale, Aonidiella aurantii.

This is a division, of application Ser. No. 886,324, filed Mar. 13,1978.

This invention relates to the synthesis of a component of the sexpheromone of the California red scale, Aonidiella aurantii (Maskell) andintermediates therefor.

The California red scale is a pest of citrus. The natural femalepheromone attracting the male red scale consists of3-methyl-6-isopropenyl-9-decen-1-yl acetate (AI) and(z)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate (AII). Roelofs etal., Nature 267, 698 (June 23, 1977).

The synthesis of the present invention can be outlined as follows:##STR1##

(S)-(+)-Carvone (III) is converted to the epoxide IV with alkalinehydrogen peroxide in methanol. Treatment of IV with dilute perchloricacid in tetrahydrofuran (THF) gives a mixture from which the keto diol Vcrystallizes. Oxidation of V with 2 equivalents of lead tetraacetate inethanol-benzene gives directly a mixture of the diastereomeric lactonesVI which are converted to the acetal ester VII with triethylorthoformate in ethanol. Lithium aluminum hydride reduction of VII givesthe alcohol acetal VIII which on reaction with p-toluenesulfonylchloride in pyridine gives the acetal tosylate IX. The tosylate is thenconverted to the bromo acetal X with NaBr in hexamethylphosphorictriamide (HMPT) and reaction with vinyl lithium in THF gives the dieneacetal XI. Hydrolysis of the acetal produces the diene aldehyde XII.This diene aldehyde is then reacted with the ylide generated from thecorresponding 3-hydroxy-1-methylpropyltriphenylphosphonium salt to givethe triene alcohols XIII. GLC analysis indicates that the Z and Eisomers are formed in the Wittig reaction in a ratio of 52:48,respectively. Acetylation of XIII with acetic anhydride in pyridinegives the corresponding triene acetate XIV.

Separation of the R,Z and R,E isomers of XIV is obtained by preparativeGLC separation of the mixture. The optical purity of the synthetic R andS isomers of II was determined by the following outlined technique:##STR2##

Thus, the R diene aldehyde XII was oxidized with excess Jones reagent togive the corresponding acid, XV. This acid was then converted to theacid chloride (SOCL₂, ether, catalytic dimethylformamide), which ontreatment with (R)-(+)-1-(1-naphthyl)ethylamine gave the amide XVI.Similarly, the corresponding diastereomer was prepared from the S isomerof XV and (R)-(+)-1-(1-naphthyl)ethylamine. These diastereomeric amideswere completely resolved by high performance liquid chromatography(HPLC) (22×0.46 cm Zorbax-SIL, DuPont, eluted with water-saturated 10%ethyl acetate in pentane at 1.8 ml/min). From such a HPLC analysis thepercentage optical purity of XVI [and hence of (R)-XIV and also of thesynthetic (R,Z)-isomer II)] was shown to be 98.4%. In a like manner theS isomers of II were shown to be of 99.0% optical purity. ##STR3##

The spectrum of AII (CS₂ ; 300 MHz) is consistent with structure II withδ values as follows: 5.71 (1H, m, "J"=7,10,16 Hz [t,d,d, respectively])4.92 (1H, d, "J"=16 Hz), and 4.87 (1H, d, "J"=10 Hz) [H₂ C═CH-CH₂ --];5.12 (1H, t, "J"=6 Hz) [R₂ C═CH-CH₂ --]; 4.7 (1H, s) and 4.64 (1H, s)[R₂ C═CH₂ ] 3.95 (2H, t, J=7.5 Hz) and 1.92 (3H, s) ##STR4## 2.27 (2H,t, J=7 Hz) ##STR5## 1.9-2.1 (5H, m, allylic); 1.69 (3H, s) and 1.60 (3H,s) ##STR6## and 1.39 ppm (2H, m).

The following examples are provided to illustrate the practice of thepresent invention. Temperature is given in Centigrade. TLC denotes thinlayer chromatography and GLC denotes gas liquid chromatography.

EXAMPLE 1

To 100 g (0.67 mol) d-carvone (III) in 600 ml methanol at 10° was added170 ml (2 mol) 30% H₂ O₂ and then 55 ml 6 N NaOH slowly (0.33 mol),maintaining the temperature in the range 10°-20°, with dry-ice bath.After about 3 hours, the reaction was poured into about 800 ml water andextracted with ether (3X 300 ml). The combined ether fractions werewashed with saturated NaCl, dried over calcium sulfate androtoevaporated to give the epoxide IV, b.p. 76°-78°.

A mixture of 80.0 g of the above epoxide, 1500 ml THF, 1100 ml water and100 ml 7% HClO₄, under nitrogen, was raised to temperature of 60°-65°and then 700 ml THF was added. After about 20 hours, 50 ml 7% HClO₄ and400 ml water were added. After 55 hours, the reaction was rotoevaporatedto remove most of the THF. The residue was poured into ether and sat.NaCl solution. The organic phase was washed with sat. sodium bicarbonateand sat. NaCl, dried over calcium sulfate and solvent removed. Theresidue was stirred with 100 ml hexane and 70 ml ether and thenfiltered. The solid was washed with additional hexane/ether (10/7) anddried under cacuum to give the keto diol V, m.p. 104°-107°.

To 20.0 g (0.109 mol) diol V, 350 ml benzene and 150 ml ethanol, cooledin an ice-bath, was added 120 g of 85% lead tetraacetate (0.23 mol) overabout 20 minutes with stirring. After about 2 hours, the reactionmixture was filtered and ether added to the filtrate, which was thenwashed with sodium sulfite solution, 2 N sodium carbonate and sat. NaCl,dried over calcium sulfate and solvent evaporated to give the lactonesVI. [IR (CCl₄) 3080 (C═CH₂), 1760 cm⁻¹ (C═O); NMR (CDCl₃,δ) 5.35 (m 1H),4.83 (br s, 2H), 1.77 (br s, 3H), and 1.23 ppm (t, 3H, J=7 Hz)].

To 19.0 g (0.103 mol) lactone VI and 150 ml ethanol, under nitrogen, wasadded 19.0 g (0.128 mol) triethylorthoformate and 0.4 gp-toluenesulfonic acid. After about 22 hours, the mixture wasconcentrated by evaporation and poured into ether. The organic phase waswashed with sat. sodium bicarbonate and sat. NaCl, dried over calciumsulfate and rotoevaporated to yield the acetal ester VII. IR (CCl₄) 3075(H₂ C═C), 1740 cm⁻¹ (C═O) NMR (CDCl₃,δ) 4.80 (br s, 2H), 4.45 (t, 1H,J=6 Hz), and 1.70 ppm (br s, 3H).

To 25.0 g (0.097 mol) acetal ester VII and 300 ml dry THF, at 0° undernitrogen, was added 58 ml 70% sodium bis(methoxyethoxy)aluminum hydride(40.4 g hydride, 0.2 mol). After several hours, the reaction wasquenched by addition of water and poured into ether and water. Theaqueous phase was back extracted with chloroform. The combined organicfractions were washed with sat. NaCl, dried over calcium sulfate andsolvent removed under vacuum to give alcohol acetal VIII. IR (CCl₄) 3630and 3490 cm⁻¹ (OH); NMR (CDCl₃, δ) 4.82 (br s, 2H), 4.47 (t, 1H, J=6Hz), 1.68 (s, 3H), and 1.20 ppm (t, 6H, J=7 Hz).

EXAMPLE 2

A mixture of 6.7 g (35 mmol) p-toluenesulfonyl chloride, 20 ml drypyridine, at 0° under nitrogen, and 5.0 g (23 mmol) of alcohol acetalVIII was stirred for about 16 hours. A small amount of ice was added andafter stirring, poured into ether and water. The organic phase waswashed with sat. CuSO₄ and sat. NaCl, dried over calcium sulfa andevaporated to give acetal tosylate IX. NMR (CDCl₃,δ) 4.40 (t, 1H, J=5.5Hz), 3.98 (t, 2H, J=6.5 Hz), 2.47 (s, 3H), and 1.18 ppm (t, 6H, J=7 Hz).

To 7.6 g (20.5 mmol) acetal tosylate IX and 30 ml dry HMPT, at roomtemperature under nitrogen, was added 3.1 g (30 mmol) sodium bromide.The reaction was stirred about 16 hours and poured into hexane/water.The aqueous phase was back extracted with hexane. The combined organicfractions were washed with water, dried over calcium sulfate and solventevaporated to yield bromide X. Five grams (18 mmol) of the bromide in 15ml THF was slowly added to a solution, at -20° under nitrogen, of 7 ml(21 mmol) 3 M vinyl lithium in THF and 40 ml THF. After 30 min. thecooling bath was removed and the reaction stirred at room temperaturefor 7 hours. A small amount of water was added and the reaction pouredinto ether/water. The aqueous phase was back-extracted with ether. Thecombined ether fractions were washed with sat. NaCl, dried over calciumsulfate and solvent evaporated to yield diene acetal XI. NMR (CDCl₃,δ)4.43 (t, 1H, J=6 Hz), 1.62 (d, 3H, J= 1 Hz), and 1.18 ppm (t, 6H, J=7Hz).

EXAMPLE 3

A mixture of 1.39 g (6.15 mmol) diene acetal XI, 40 ml acetone, 20 mlwater and 150 ml toluenesulfonic acid was heated at 45° for 5 hours. Thereaction was poured into sat. sodium bicarbonate and ether. The aqueousphase was back-extracted with ether and the combined ether phases werewashed with sat. NaCl, dried over calcium sulfate, and solventevaporated to yield the diene aldehyde XII. IR (CCl₄) 3080 (H₂ C═C),1730 cm⁻¹ (c═O); NMR (CDCl₃,δ) 9.75 (t, 1H, J=2 Hz) and 1.67 ppm (br s,3H).

To 2.6 g (6.5 mmol) 3-hydroxypropyltriphenylphosphonium bromide in 30 mldry THF at 0° under nitrogen was added 8.05 ml (12.9 mmol) 1.60 Mn-butyllithium in hexane. After about 30 min, 920 mg (6.5 mmol) methyliodide was added. The reaction mixture was stirred for about 30 min and4.0 ml (6.4 mmol) 1.60 M n-butyllithium in hexane was added. After 15min, diene aldehyde (0.80 g) XII in THF was added. After 2 hours,several ml of water was added and then the reaction poured intoether/water. The aqueous phase was back-extracted with ether. Thecombined ether fractions were washed with sat. NaCl, dried over calciumsulfate and solvent evaporated. The residue was applied to thin layerchromatography plates, eluted with 17% ethyl acetate/hexane, and thealcohol band removed to yield the triene alcohols XIII. IR (CCl₄) 3625and 3540 (OH), 3075 cm⁻¹ (H₂ C═C); NMR (CDCl₃,δ) 3.67 (t, J=7 Hz), 3.61(t, J=6.5 Hz), and 1.62 and 1.70 ppm (both br s, 6H).

A mixture of the triene alcohols XIII (500 mg, 2.42 mmol), 3 ml pyridineand 0.7 ml acetic anhydride, under nitrogen, was heated to 60° for 3hours. Then a small amount of ice was added followed by stirring for 30minutes. The reaction was poured into ether and sat. CuSO₄ solution. Theorganic phase was washed with CuSO₄ solution, sodium carbonate and sat.NaCl, dried over calcium sulfate and solvent evaporated to give trieneacetates XIV. IR (CCl₄) 3080 (C═CH₂), 1745 cm⁻¹ (C═O); NMR (CDCl₃,δ)4.10 and 4.13 (two t, 2H, J=7 Hz), 2.03 (s, 3H), and 1.62 and 1.70 ppm(both br s, 6H).

What is claimed is:
 1. The compound, 3-isopropenyl-6-heptenoic acid. 2.The 3R-enantiomer of the compound of claim 1.